ASHM Report Back

Clinical posts from members and guests of the Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine (ASHM) from various international medical and scientific conferences on HIV, AIDS, viral hepatitis, and sexual health.

In its 15th year, the IAS initiative Cure Towards an HIV Cure, held its forum prior to the IAS conference. This year the forum expanded its attention to Cancer given the similarities between the fields and limited formal collaboration. Many immunological therapies used for Cancer treatment may also have a role in HIV Cure. As our HIV patients age with suppressed HIV viremia they are experiencing more cancer. Cancer and Persistence of HIV share many features and goals of treatment so that a shared approach to research will only enhance outcomes for both groups and especially for HIV patients with cancer. This latter group are currently serving as an “observational cohort” as we try to understand the effects of immune checkpoint blockers – both efficacy and adverse effects, short and long term – in people living with HIV and its associated additional immune dysfunction. Cell surface marker CD32a on CD4 cells has now been recognised as a potential marker for HIV DNA levels. The concept of measurement of residual disease burden after treatment is being borrowed from oncology to aid in the understanding of achieving durable remission. Focus on the change in approach to treatment of cancer from drugs targeting cancer cells to the approach now of targeting the host’s own immune cells to kill the cancer cells. Understanding of how anti-cancer drugs affect the HIV reservoir was progressed, as was comparisons of the effects of immunotherapy for cancer and in HIV. The class and availability of different “immune checkpoint inhibitors” is exploding in cancer treatment, and as HIV patients with cancer start to receive these drugs for their cancer, the effects on latency reversal of HIV are being carefully documented. Interferons are being revisited, effects of stem cell transplants and gene therapy to improve the immune response to cancer are also being explored – but all early days and case reports in the main. One of the most important sessions was a round table discussion on clinical trial design once the safest better candidates have been identified – protocols with a common trial design, agreed endpoints (most likely composite) and biomarker measurement, need to be established. Access has been identified as a major consideration, community engagement vital, understanding of how analytical treatment interruptions will be used and viewed by participants and the financial “toxicity” of HIV Cure were identified. We continue to make strides towards our ultimate goal.

The efficacy of the HIV medication Truvada as an HIV prophylaxis is very well established in the sexual health and HIV treatment/prevention world. Truvada, better known as PrEP in the HIV prevention context, is made up of the two antiviral medications emtricitabine 200 mg and tenofovir disoproxil fumarate 300 mg.

The implementation of PrEP in Asian countries is struggling to get underway in sufficient numbers and the primary reason for this is mostly due to cost. Although, there are other very significant barriers to getting at risk populations on the medication, as a way to reducing the transmission of HIV. Another barrier is that clients do not want to be seen attend clinics for fear of being ‘outed’ as either belonging to the men who have sex with men group (MSM), being transgender (TG) or being recognized as a person who injects drugs, all of which carry extreme risk in certain areas of Asia. The most clearly at risk MSM age group is those 20-24, where the greatest number of new infections are found in Asia.

There are some extremely concerning issues surrounding all of the above at risk groups. Firstly, the MSM group. Currently in Indonesia there are serious concerns arising over some parts of Indonesia whereby gay and bisexual men are being punished and prosecuted for having sex with men or engaging in group sex. Another group suffering stigma and discrimination (and are therefore having problems accessing services) are transgender individuals. The social scientist Martin Choo explained that there have been cases of clinics proving care to transgender clients (an understandably highly disadvantaged group disproportionately affected by serious health concerns) and due to either conflict and or discrimination within the clinic, information was released to the public about the identities of the transgender clients receiving care. This has obviously resulted in a serious breach to personal safety and the ability of those individuals to return to services and receive the care they need. Another example of a serious barrier to accessing PrEP in the Asian region is in the Philippines, where their current stance on drug laws is so severe that services providing NSP paraphernalia can be used against workers, resulting in incarceration. These, and other serious problems in the region are commonplace and illustrate how much work needs to be done to change attitudes and get governments and communities to see the benefits of PrEP (not to mention NSP programs, transgender health and the sex worker communities). Other barriers include a very recent redaction of funds to Vietnam by the USA and accepted public violence towards MSM/TG and other minority groups.

At this stage and from the talks at the APACC, it appears that Thailand, Taiwan and Vietnam are the countries that have so far managed trials or programs whereby these at risk populations can access PrEP and therefore work towards preventing the spread of HIV. I do not believe that any of these countries have any more than a few hundred clients accessing this prophylactic medication. It makes the situation in Australia seem like a paradise for health professionals, clients and governments, whereby there are somewhere in the vicinity of 8000 people accessing this medication. This amazingly positive number of people and positive situation overall (where attitudes allow for this to happen on an individual level and at a state government level) is believed so far to have resulted in a reduction of HIV infections by about 25%, which is a conservative number. One speaker mentioned that the gay dating app Blued has somewhere in the vicinity of 27 million users in China. This is an enormous number of at risk clients and a group that would very greatly benefit from the medication and make a huge difference in the global fight against HIV.

There is currently a global target in place (apologies I am not aware of the origin of this statistic) to get 3 million people at substantial risk on PrEP. As of October 2016, only around 100,000 people were able to access the medication. It is very clear that a lot of work needs to be done to change attitudes to PrEP, develop protocols, convince governments to assist in funding such programs and using this very effective medication to reduce the global burden of HIV.

I would like to present my interpretation of a session at the HIV Clinical Forum (for integrate inhibitors) held on the 31st May 2017. I believe this sessions was not as widely attended as the first day of the Asia Pacific AIDS and Confections Conference (APACC). Specifically, I will focus on an ‘HIV prevention 2.0’ talk by Dr Charles Boucher, who is a virology professor in Rotterdam and the scientific director (and owner) of Virology Education, Utrecht, Netherlands. Virology Education is the organisation that put together the APACC event in Hong Kong right now and have at least 8 other conferences throughout the year in a number of international locations.

Please note that the information presented here is not exhaustive and is limited by the speed at which I was able to take notes and my individual interpretation.

Dr Boucher began his talk speaking about the HIV prevention methods of circumcision, condoms, PrEP, PEP and ART. I was quite interested in the addition of circumcision to this list, because in my experience it is not often included in such lists. The evidence that male circumcision reduces HIV infections is quite strong.

The cost of prevention methods is a very significant problem across the world and very specifically in developing countries. Dr Boucher commented that governments struggle to understand the medication PrEP and do not see its effectiveness in reducing the cost of HIV ART and associated health care costs. I believe that some of the attendees and presenters have mentioned that PrEP comes at a cost of approximately $1US per day, which is completely unattainable to many persons around the world. Among these people are severely disadvantaged groups such as sex workers, transgender individuals and PWID.

Targeting strategies for each at risk population was a point made repeatedly by this speaker. It is interesting to note that the percentages of specific population transmission routes varied considerably between countries attending this conference. The sexual transmission groups in Australia are dominated by the MSM community whereas in China the most common group transmitting the virus are heterosexuals (66%).

The doctor concluded by saying that increasing annual testing and the uptake of PrEP in the high risk population of MSM is very important. Lack of substantial reductions in transmission is not due to ineffective ART provision or inadequate retention, rather, it is due to frequent early transmission. Dr Boucher seemed dubious as to achieving the goal of zero new HIV infections in 2030 and recommended closer collaboration between public health professionals and HIV health care providers. He also repeated his recommendation of targeted strategies and intervention approaches with specific reference to sexual/virological networks.

NB. I would like to say that the doctor also spoke about flyogenetics, analysis of sequences, resistance genotyping and viraemia but I am unable to accurately represent this information. I am very much looking forward to all of these presentations being accessible online and organisers of this even have informed me that 80% or more of the presentations should be available within 2-3 weeks.

Dr Carl June presented how novel therapeutics have the potential for an HIV cure. His work in the development of Chimeric Antigen Receptor (CAR) T cells have been instrumental in the cure of lymphoid malignancies. There are similarities in CD4 cell dysfunction between cancer, which causes exhaustion of T cells, and HIV, which causes deletion of HIV specific cells.

CAR T cell therapies use synthetic biology, tools of genetic engineering and genome editing to install a competent immune system into an immunocompromised host. In cancer therapy, an individual's T cells are harvested and geneticically engineered to make the T cells stably express CAR, conferring novel antigen specificity. They are reinfused into the patient to become personal "serial killer" cells. In almost 400 patients accumlating 1500 patient years, there have been no acute T cell toxicity events (ie. no conversion to acute leukaemia). Success has been seen out to 5 years with complete cure of a paediatric patient with advanced ALL and an older adult with extensive CLL.

Unfortunately there are no CAR T cell trials in HIV currently in progress, but it is likely to be an area of future research, with work towards an HIV cure.

The issues faced with this sort of technology are based around time, cost and the need for an individual's cells to be genetically engineered for each patient. Consideration of a blood bank model or central manufacturing strategy could advance implementation. Automated genetic engineering methods could allow CAR T cell treatments to be scalable, with lower coats and increased access. A government-industry-philanthropic partnership for combined funding could be a way ahead.

Dr Jintanat Ananworanich presented the first plenary session on the emerging potential for an HIV cure. She disussed how information gained from adult and infant studies showed that early treatment, rapid viral suppression and sustained seronegativity results in less reservoir seeding and an extended time to viral rebound following cessation of ART. This has important implications for targeting persistent virus, particularly replication competent virus.

Early attempts at a "shock and kill" strategy have been unsuccessful at significantly decreasing the amount of reservoir virus or killing affected cells. Fture strategies are likely to employ the use of multiple Latency Reversing Agents (LRA), the use of new classes of LRA and combination use with immune therapies. Trials in animal models using a TLR7 agonist with Ad26MVA vaccine demonstrated promise in animal models, with a reduced viral load in monkeys infected with SHIV following ART discontinuation.

Preliminary trials of VRC01, a broadly neutralising antibody (bNAb) has also shown to be ineffective. However, the more potent VRC07-523LS bNAb, combinations of bNAbs or combination with vaccines are more effective approaches being tried. A combination of VRC07+PGT121 (a vaccine) given to infant macaques 1-2 days after SHIV infection led to a complete clearance of the virus.

The final messages Dr Ananworanich presented were that new methodologies need to be considered in order to facilitate research, notably

Consider parallel animal and human studies for combination therapies;

Testing combinations with the same animal model;

Streamlining the regulatory pathways for the use of agents for different indications; and